Method of preparing organomagnesium compounds

ABSTRACT

The present invention is directed to a reagent for use in the preparation of organomagnesium compounds as well as to a method of preparing such organomagnesium compounds. The present invention furthermore provides a method of preparing functionalized or unfunctionalized organic compounds as well as the use of the reagents of the present invention in the preparation of organometallic compounds and their reaction with electrophiles. Finally, the present invention is directed to the use of lithium salts—LiY in the preparation of organometallic compounds and their reactions with electrophiles and to an organometallic compound which is obtainable by the disclosed method.

TECHNICAL FIELD

The present invention is directed to a reagent for use in thepreparation of organomagnesium compounds as well as to a method ofpreparing such organomagnesium compounds. The present inventionfurthermore provides a method of preparing organic compounds. It furtherprovides the use of the reagents of the present invention in thepreparation of organometallic compounds and their reaction withelectrophiles. Finally, the present invention is directed to the use oflithium salts—LiY in the preparation of organometallic compounds andtheir reactions with electrophiles and to an organometallic compoundwhich is obtainable by the disclosed method.

BACKGROUND OF THE INVENTION

Polyfunctionalized organometallics are important intermediates in modernorganic synthesis.^([1])

One of the best preparative methods of these reagents is thehalogen-metal exchange reaction. Whereas the Br/Li-exchange is a fastreaction which occurs at low temperature, the correspondingBr/Mg-exchange is considerably slower which is a severe syntheticlimitation for several reasons:

-   (i) the exchange requires higher reaction temperature and therefore    is not compatible with many functional groups,-   (ii) the slow Br/Mg-exchange especially on electron-rich aromatic    bromides is in competition with the elimination of HBr from the    alkyl bromide also produced during the reaction (usually isopropyl    bromide) and therefore, results in low yields. A catalysis of the    Br/Mg-exchange would be a highly desirable process. Recently, the    inventors have shown that highly functionalized aryl- and    heteroaryl-magnesium halides can be readily prepared by using an    iodine-magnesium exchange reaction.^([2]) As exchange reagent    i-PrMgX (X═Cl, Br) proves to be most convenient. In some cases, this    exchange reaction could be extended to some aryl and heteroaryl    bromides when a powerful electron-withdrawing and (or) a chelating    group was present to coordinate i-PrMgX and make the Br—Mg exchange    “intramolecular”.^([3])

Basically, the I/Mg-exchange reaction is an excellent method forpreparing functionalized aryl and heteroaryl compounds. It has as maindrawback the need of using sometimes unstable, often expensive orcommercially not available organic iodides. The alternative of usingaryl bromides as substrates for the Br/Mg-exchange is known, but wasstrongly limited to only highly reactive aryl bromides (bearing severalelectron-withdrawing groups) due to the low rate of the exchangereaction using either i-PrMgCl or i-Pr₂Mg.

Therefore, it is a problem underlying the present invention to providean improved method of preparing organomagnesium compounds. It is afurther problem underlying the present invention to provide anorganomagnesium compound, which has a higher reactivity with anelectrophile (E+).

These problems are solved by the subject-matter of the independentclaims. Preferred embodiments are set forth in the dependent claims.

SUMMARY OF THE INVENTION

The inventors found that by using the mixed organometallicR¹(MgX)_(n).LiY, a fast exchange reaction occurs leading to the desiredGrignard reagents in high yields under mild conditions and allowing thepreparation of many functionalized Grignard compounds which werepreviously only available via Br/Mg-exchange reactions in mediocreyields. The method of the present invention considerably facilitates inparticular the preparation of aryl-, heteroaryl-, alkenyl-, alkinyl oralkyl-magnesium compounds and finds broad applications in university aswell as in industrial laboratories for large scale use. Basically, themethod of the present invention corresponds to the following reactionscheme:

According to a first aspect, the invention is directed to a reagent foruse in the preparation of organomagnesium compounds, the reagent havingthe general formulaR¹(MgX)_(n).LiYwherein

-   n is 1 or 2;-   R¹ is a substituted or unsubstituted C₄-C₂₄ aryl or C₃-C₂₄    heteroaryl, containing one or more heteroatoms as B, O, N, S, Se, P,    F, Cl, Br, I, Si; linear or branched, substituted or unsubstituted    C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl or C₂-C₂₀ alkinyl; or substituted or    unsubstituted C₃-C₂₀ cycloalkyl; or a derivative thereof;-   X and Y are independently or both Cl, Br or I, preferably Cl;    HalO_(n) (where n=3, 4); carboxylate of formula RCO₂; alkoxide or    phenoxide of formula RO; dialkoxide of formula LiO—R—O; disilazide    of formula (R₃Si)₂N; thiolate of formula SR; RP(O)O₂; or SCOR; where    R is defined as R¹ above;-   C₁-C₂₀ linear or branched, substituted or unsubstituted alkyl or    C₃-C₂₀ cycloalkyl amine of formula RNH; dialkyl/arylamine of formula    R₂N (where R is defined as above or R₂N represents a heterocyclic    alkylamine); phosphine of formula PR₂ (where R is defined as above    or PR₂ represents a heterocyclic phosphine); O_(n)SR (where n=2 or 3    and R is defined as above); or NO_(n) (where n=2 or 3); or X═R¹ as    defined above; and a derivative thereof.

It is noted that X and R¹ usually will be the same substituent in thecase of X═R¹, however may also be different in the scope of thedefinition indicated for R¹.

It is explicitly noted that the present invention also comprisescompounds of formula XMg—R¹—MgX.LiY (i.e., where n=2). Furthermore,whenever “R₂” is indicated in this application (for example in R₂N orPR₂), both R's may be the same or may be different according to thedefinition indicated above.

Additionally, it surpisingly turned out that the exchange rate usingR¹(MgX)_(n).LiY can be further enhanced, if X═R¹. This reagent isachieved by addition of polyethers or polyamines that lead to theformation of new reagent (R¹)₂Mg.LiY.

Thus, in a preferred embodiment, the reagent is (R¹)₂Mg.LiY.

The mechanism involved in this unexpected finding may be explained asfollows:

It is noted that this system usually requires to use at least onesolvent as outlined below and at least one additive (see also below).For example THF might be used as a solvent alone or in combination withother solvents, and a crown-ether as outlined above might be used asadditive, which is directly involved in the formation of the reagent is(R¹)₂Mg.LiY.

There might be exceptions to that general rule in that some solvents maybe used also as additive or vice versa. For example, it is possible toprepare (R¹)₂Mg.LiY in pure dioxane as outlined below.

Dioxane has several advantageous properties, it is a, for example,cheap, non-toxic, industrial, not easily flammable, high boiling, notvery hydroscopic solvent that is easy to handle and to make dry—thus apractically ideal solvent and additive. And, it serves as a suitableadditive and solvent in the above reactions.

As an example for the above reaction, the reagent is made in situ bytreating simply a solution of i-PrMgCl.LiCl with a crown-ether such as15-crown-5 (which gives the best result; see entry 4 of Table 3) or moregenerally with another polyether or polyamine, see Table 3. Remarkably,and as mentioned above, the cheapest way to achieve the rate enhancementis to use the addition of dioxane (10% vol) which lead to 100% ofconversion (4-bromoanisole to 4-methoxy-phenylmagnesium chloride) after24 h reaction time. For comparison the performance of the same reactionwith i-PrMgCl.LiCl in THF gives only 31-39% conversion after the sametime. It is also important to notice that the addition of 15-crown-5 ordioxane to i-PrMgCl without LiCl does not lead to any rate enhancement.

Thus, the addition of 1,4-dioxane (or related polyethers like oligo- orpolyethyleneglycol ethers or polyamines) will further enhance exchangereactions such as the Br/Mg—exchange and allow to convert e.g. bromidesinto the corresponding Grignard reagents under conditions which beforeled to uncomplete reaction. Further explanations for this may be foundin chapter “Examples”.

According to one embodiment, the reagent comprises R¹(MgX)_(n) and LiYin a molar ratio of between 0,05-6,0.

According to a preferred embodiment, Y is Cl in R¹(MgX)_(n).LiY or LiY.In an even more preferred embodiment, R¹(MgX)_(n).LiY is i-PrMgCl.LiClor sec-BuMgCl.LiCl. The preferred molar ratios between i-PrMgCl orsec-BuMgCl and LiCl are 0,05 to 6,0.

According to a further preferred embodiment, Y in R¹(MgX)_(n).LiY or LiYis tert-butylate or sec-butylate. Other lithium salts like lithiumperchlorate, lithium acetylacetonate, lithium bromide, lithium iodideand lithium tetrafluoroborate are also included in this invention,however, are less preferred embodiments.

According to a second aspect, the present invention provides a method ofpreparing organomagnesium compounds, comprising the following steps:

-   a) providing a compound having the general formula:    R²A;    wherein-   R² is defined as R¹ or is a substituted or unsubstituted metallocene    such as ferrocene; or a derivative thereof.-   A is H, Cl, Br, I, preferably Br, or a group of the general formula:    S(O)_(n)—R³    wherein-   n=0, 1 or 2-   or a group of the general formula:    P(O)R³ ₂    wherein R³ independently is defined as R¹ above. It is noted that R³    in this context may be the same or different.-   or P(O)R³ ₂ represents a heterocyclic phosphinoxide;-   b) providing a reagent according to the formula R¹(MgX)_(n).LiY as    defined above;-   c) reacting the compounds provided in step a) and b) under suitable    conditions; thereby obtaining the respective organomagnesium    compound.

The organomagnesium compound obtained in c) can additionally beisolated.

It is noted that, if R² is an aryl or heteroaryl compound, it may besubstituted by one or more groups FG, wherein FG is preferably selectedfrom F, Cl, Br, CN, CO₂R, OR, OH, NR₂, NHR, NH₂, PR₂, P(O)R₂, CONR₂,CONHR, SR, SH, CF₃, NO₂, C═NR, R (wherein R is defined as R¹ above).Preferred examples of R²A are bromonapthalene, bromophenanthrene,bromoanisole, bromothiophene, bromothiazole, bromopyridine,1-bromo-3-fluorobenzene, 3-bromobenzothiophene, 1,2-dibromobenzene,1,2,4 tribrombenzene and derivatives thereof as well as the furthercompounds disclosed hereinafter.

Principally it is possible to use all kinds of functional groups FG thatare, for example, cited in the following references, but are not limitedthereto:

-   a) Handbook of Grignard reagents; edited by Gary S. Silverman and    Philip E. Rakita (Chemical industries; v. 64).-   b) Grignard reagents New Developments; edited by Herman G. Richey,    Jr., 2000, John Wiley & Sons Ltd.-   c) Methoden der Organischen Chemie, Houben-Weyl, Band XIII/2a,    Metallorganische Verbindungen Be, Mg, Ca, Sr, Ba, Zn, Cd. 1973.-   d) The chemistry of the metal-carbon bond, vol 4. edited by Frank R.    Hartley. 1987, John Wiley & Sons.

According to a further embodiment, the reagent of the general formulaR¹(MgX)_(n).LiY is provided by reacting R¹X, Mg and LiY or by reactingR¹(MgX)_(n) and LiY, or by reacting R¹Li and MgXY. It is noted that somecomponents for use in this reaction are commercially available and thus,are not required to be synthesized de novo (for example, i-PrMgCl forR¹MgX is commercially available from Aldrich or Strem CAS [1068-55-9])

According to an embodiment, the reagent provided in step b) is used in amolar amount of 0,4-6,0 mole per mole of the compound provided in stepa). In general, the reagent of the present invention having the generalformula R¹(MgX)_(n).LiY can be added up to 6,0 mole of the reagent to 1mole of compound provided in a) (general formula R²A). The lower limitof 0,4 mole per mole R²A means that the effects of the presentinvention, i.e. the spectacular rate increase in the conversionreaction:

may not be achieved, if values lower than this limit will be used.

It is noted that in the above formula, n may be different inR¹(MgX)_(n).LiY and R²(MgX)_(n).LiY.

The above reaction is carried out in a suitable solvent. Preferably, thesolvent, in which R¹(MgX)_(n).LiY is dissolved is an inert aproticsolvent, for example tetrahydrofuran, diethyl ether,2-methyltetrahydrofuran, dibutyl ether, tert-butylmethyl ether,dimethoxyethane, dioxane, triethylamine, pyridine,ethyldiisopropylamine, dichlormethane, 1,2-dichlorethane,dimethylsulfide, dibutylsulfide, benzene, toluene, xylene, pentane,hexane or heptane, or combinations thereof and/or solvents usually usedfor performing of Grignard reactions that are indicated in theliterature cited above.

As outlined above, adding one or more additives to the solvent may yieldan improved reagent (R¹)₂Mg.LiY. This additive may be selected frompolyethers or polyamines, in particular crown ethers, dioxanes, oligo-or polyethylenegylcol ethers, derivatives of urea, amides of formulaRCONR₂ (where R is defined as in claim 1, radicals may be same ordifferent), most preferably 1,4-dioxane or 15-crown-5 or combinationsthereof. Further examples of additives which might be used in thepresent invention are listed in Table 3, below.

According to a further embodiment, the above solution of R¹(MgX)_(n).LiYis 0,05 to 3,0 M, preferably 1,0-2,5 M. As a general rule, the higherthe concentration of the solution is, the better the overall reactionwill work. However, generally, more than 3 M solutions ofR¹(MgX)_(n).LiY will no more be soluble and thus will not function inthis invention.

The use of R¹(MgX)_(n).LiY as a powder (without solvents or withcoordinated solvents) is also possible and especially convenient forstorage.

According to a further aspect, the invention provides a method forpreparing functionalized or unfunctionalized organic compounds,comprising steps a)-c) as defined above, and

-   d) reacting the obtained organomagnesium compound with an organic or    inorganic electrophile (E+) or (E).

The reaction follows the reaction scheme:

Examples of electrophiles which are commonly used for the reaction withGrignard reagents are cited in references a)-d) mentioned above, but notlimited thereto.

Specific examples for the electrophile are RCHO, RCOX, X_(n)PR_(3-n)(n=1, 2, 3), X_(n)P(O)R_(3-n) (n=1, 2, 3), RX, RCO₂R, RCN,R_(n)Si—X_(4-n) (n=0, 1, 2, 3), R_(n)SnX_(4-n) (n═0, 1, 2, 3) orRSSO_(n)R (n=0, 1, 2), RNO₂, RNO, RN═NSO₂R, RC═NR, B(OR)₃,

wherein

-   X is a halogen or S(O)_(n)R group, wherein n=0, 1 or 2, and R is    generally defined as R¹ above.

Again, it is noted that, where two or three R's are contained in oneformula, they can be the same or different from each other.

However, the invention is not restricted to these examples and improvedreactions of the Grignard reagents complexed with LiY with variouselectrophiles are observed for all types of electrophiles.

The methods mentioned above are performed at a temperature in a rangebetween −78° C. to 80° C., preferably at room temperature. The upperlimit of the temperature range generally is the boiling temperature ofthe respective solvent used.

According to a further aspect the invention is directed to the use ofthe reagent R¹(MgX)_(n).LiY in the preparation of organometalliccompounds and their reaction with electrophiles.

A further aspect of the invention is directed to the use of LiY in thepreparation of organometallic compounds and their reaction withelectrophiles, wherein Y is defined as above. It is noted that inparticular LiCl turned out to dramatically increase the conversion ratesin the above exchange methods. For comparison, see enclosed Table 2.

According to a final aspect, the invention provides an organometalliccompound, which is obtainable by the method in accordance with thesecond aspect as defined above. It is noted that the complexed productof this reaction, i.e. a product of general formula R²(MgX)_(n).LiY, hasa much higher reactivity with electrophile (E+) or (E) than the priorart reagents and also its solubility in the respective suitable solvents(see above) is superior.

Thus, by the methods of the present invention it is possible to achieveconversion rates of up to 100% compared to only mediocre yields of theprior art methods.

The present invention will be further described with reference to thefollowing figures and examples; however, it is to be understood that thepresent invention is not limited to such figures and examples.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is showing the conversion of 4-bromobenzonitrile at −7° C. to4-cyanophenylmagnesium bromide.

FIG. 2 is showing the conversion of 4-bromoanisole at room temperatureto 4-methoxyphenylmagnesium bromide.

FIG. 3. Grignard reagents prepared in over 90% by the Br/Mg exchangeusing i-PrMgCl.LiCl (the reaction conditions are given below eachformula).

DETAILED DESCRIPTION OF THE INVENTION

The present invention will now be described more fully hereinafter withreference to the accompanying figures. The following embodiments arerather provided so that this disclosure will be thorough and complete,and will fully convey the scope of the invention to those skilled in theart.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. All publications and otherreferences mentioned herein are incorporated by reference in theirentirety.

As used herein, the terms “alkyl”, “alkenyl” and “alkinyl” refer tolinear and branched, substituted and unsubstitued C₁-C₂₀ compounds.Preferred ranges for these compounds are C₁-C₁₀, preferably C₁-C₅ (loweralkyl) and C₂-C₁₀ and preferably C₂-C₅, respectively, for alkenyl andalkinyl. The term “cycloalkyl” generally refers to linear and branched,substituted and unsubstitued C₃-C₂₀. Here, preferred ranges are C₃-C₁₅,more preferably C₃-C₈.

The term “aryl” as used herein refers to substituted or unsubstitutedC₄-C₂₄ aryl. By “heteroaryl”, a substituted or unsubstituted C₃-C₂₄heteroaryl, containing one or more heteroatoms as B, O, N, S, Se, P, ismeant. Preferred ranges for both are C₄-C₁₅, more preferably C₄-C₁₀.

The inventors now found that it is possible to catalyze exchangereactions, for example the Br/Mg-exchange reaction by using the complexR¹(MgX)_(n).LiY, for example

i-PrMgCl.LiCl. As an example, 1-bromo-3-fluorobenzene (1a) undergoesonly a slow incomplete exchange reaction with i-Pr₂Mg (1.1 equiv, rt, 3h) leading after the reaction with benzaldehyde to the correspondingalcohol 2a in 50% isolated yield.^([3a]) On the other hand, the reactionwith i-PrMgCl.LiCl under the same conditions provides the intermediatemagnesium reagent 3a with 95% yield as judged by GC-analysis usingtetradecane as internal standard. After a reaction with benzaldehyde,the alcohol 2a is obtained in 85% isolated yield (Scheme 1).

Various fluoro- and chloro-substituted aryl bromides are readilyconverted into the corresponding magnesium reagents at room temperatureusing i-PrMgCl.LiCl. The conversion is completed without 0.5-3 h whichis in strong contrast with the previous procedure involving i-PrMgCl ori-Pr₂Mg (Scheme 2).

Similarly, this catalysis can be applied to heterocyclic systems like2,6-dibromopyridine (1b). This dibromide requires also the use ofi-Pr₂Mg^([3a]) or i-PrMgCl^([3f]) for performing the Br/Mg-exchangereaction. Under these conditions, the reaction with benzaldehydeprovides the desired alcohol 2ba in only 42% yield.^([3f]) We haveobserved again the superiority of i-PrMgCl.LiCl as exchange reagent andhave observed a conversion of 92% after reaction time of 1 h at 25° C.whereas the use of i-Pr₂Mg requires a reaction time of 4 h. Using thenew reagent i-PrMgCl.LiCl, the desired reaction product (2ba) isobtained in 89% isolated yield (Scheme 1). Also good results wereobtained in the reactions of formed Grignard reagent (3b) from2,6-dibromopyridine (1b) with other electrophiles (Table 1, entries1-3). The Br/Mg-exchange in the case of 3,5-dibromopyridine can beperformed in 15 min at −10° C. and the reaction with allyl bromideprovides allylated pyridine 2ca in excellent yield (Table 1, entry 4).Less activated 3-bromopyridine can be also easily converted to thecorresponding Grignard reagent 3v within 5 min. at room temperature andled after the reaction with allyl bromide to the 3-allylpyridine 2vawith almost quantitative yield. Other heterocyclic systems such as2-bromothiophene, 3-bromothiophene, 3-bromobenzothiophene and2-bromothiazole react easily with i-PrMgCl.LiCl at room temperature andafter reaction with various electrophiles provide corresponding products2ra-2ua with good to excellent yields (Table 1, entries 29-32). Itshould be especially noted that our approach opened way for thesynthesis of different aldehydes through the reaction of Grignardreagent 3r with different electrophiles because thiazole group can beeasily converted to the aldehyde function.

This behavior is general and the use i-PrMgCl.LiCl allows a fasterBr/Mg-exchange compared to i-PrMgCl or i-Pr₂Mg. Also, it increasesdramatically the conversion leading to the desired organomagnesiumreagent without the need of an excess of reagent (usually 1.1 or 1.05equiv of i-PrMgCl•LiCl is used). Furthermore, the reactivity of theresulting magnesium reagent seems also to be improved and leads tohigher yields in trapping reactions with electrophiles. Stericallyhindered Grignard reagents bearing a substituent in ortho position like31 are obtained within 12 h reaction time at rt furnishing after theaddition of benzaldehyde the desired alcohol 21a in 90% yield (Table 1,entry 21). The more electron-rich the aromatic ring is, so slower theexchange reaction using i-PrMgCl. 2-Methoxy-1-bromobenzene (1h) ishowever converted to the desired magnesium reagent 3h in more than 90%yield after a reaction time of 24 h at rt. After its reaction withPhSSPh the thioether 2ha is obtained in 90% yield (entry 12). A range ofdifferent electrophiles reacts with these Grignard reagents after atransmetalation step with CuCN•2LiCl^([4]) allowing the performance ofallylations and acylations (entry 14).

Highly substituted chloro and methoxy aryl bromides can readily beconverted into the desired Grignard reagents 3i, j. After the reactionwith ClPPh₂ and oxidative work-up, the phosphine oxides 2ia, ja areobtained in good yields (entry 15, 16). This type of compound is ofinterest in relation with P-ligands for asymmetric catalysis.^([5]) Alsofunctions like a cyano group are tolerated. Thus, the reaction of4-bromobenzonitrile in THF at −7° C. leads to the desired arylmagnesiumreagent (3d) in only 50% conversion using i-PrMgCl whereas over 90% isobserved with i-PrMgCl•LiCl (Scheme 3). The addition of benzaldehydeprovides the alcohol 2da in 81% yield whereas allylation ofarylmagnesium reagent (3d) with allyl bromide leads to the corresponding4-allylbenzonitrile in 92% yield (entry 5,6 of Table 1). See FIG. 3 foradditional information.

The Grignard reagents 3e, f is formed within 3 h at 0° C. and showedgood yields after the reactions with various electrophiles (entries5-10). Usually unreactive compounds like bromonaphthalene andbromophenanthrene derivatives are readily converted into thecorresponding Grignard reagents 3m, n (entries 22-25) that easily reactboth with benzaldehyde (entries 22, 24) and with allyl bromide in goodyields (entry 23). After catalytic transmetallation with CuCN.2LiCl (0.2equiv.) and reaction with ethyl 4-iodobutyrate 4 h at −10° C., thedesired cross-coupling product 2nb is obtained in 81% yield (entry 25).As noticed above, various dichloro-substituted Grignard reagents like 3oand 3p can be readily prepared and react with aromatic and aliphaticaldehydes furnishing the corresponding alcohols 2oa, 2pa in 83 and 92%yield (entries 26, 27). Also ester function can be tolerated inortho-position, thus magnesium reagent 3q was prepared within 12 h at−45° C. and reaction with allyl bromide leads to the formation ofcorresponding allylated ester 2qa in 82% yield.

Remarkably, in the case of 1,2-dibromobenzenes only a mono exchangereaction occurs providing the desired Grignard reagent (3k) (−15° C.,1.5 h) in almost quantitative yield as indicated by GC-analysis ofreaction aliquots. The reaction of 2-bromophenylmagnesium chloride (3k)with 3-iodo-2-cyclohexen-1-one produces the expected enone (2kc) in 86%yield. The Grignard reagent 3k also showed good activity towardsdifferent electrophiles (entries 17-20). Various variations of thesereactions and several important new magnesium reagents are reported inentries 21-33 of Table 1.

Since the stereoselective preparation of stereochemically well definedE- or Z-alkenylmagnesium compounds is not possible by the directinsertion of magnesium into the E- or Z-alkenyl halides, theiodine-magnesium exchange reaction may be unique way of preparingstereochemically pure E- or Z-alkenylmagnesium derivatives.^([6])Recently, we have shown that the iodine-magnesium exchange reactions incase of alkenyl iodides demand the presence of electron withdrawinggroup in α- or β-position to facilitate the exchange reaction.^([7])This led us to investigate the stereoselective preparation ofalkenylmagnesium reagents via I/Mg-exchange from non activatediodo-alkenes. Thus, the reaction of (E)-1-bromohexene exchange reactionoccurs providing the (E)-1-hexenymagnesium chloride (4a) (−25° C., 10 h)in almost quantitative yield (GC-analysis of reaction aliquots). Thereaction of Grignard reagent 4a with t-BuCHO led to the formation ofcorresponding alcohols 5a with excellent yield. This remarkably lowtemperature will allow the presence of numerous functional groups. Also,we observed a fast exchange reaction with good coversion (GC) in thecase of a chiral cyclic alkenyl iodide. Subsequent reaction of magnesiumreagent 4b with allyl bromide proceed in good yield that opened theaccess to the different α-substituted chiral allylic alcohols (Scheme3).

It is also possible to do Br/Mg-exchange in vinylic systems. Thus1,2-dibromocyclopenten easily react with i-PrMgCl.LiCl at roomtemperature to produce stable Grignard reagent 4c that after reactionwith cyclohexyl aldehyde gave corresponding alcohol 5b in good yield.

Reagent 4c is completely stable at room temperature for weeks, butaddition of catalitical amounts of Cu(I) or Cu(II) leads to theformation of cyclopentine that in the presence of additional equivalentof magnesium or lithium compounds reacts with the formation of newGrignard spieces 4d,e. Addition of benzaldehyde gave correspondingalcoholes in good yields.

Other lithium salts like lithium perchlorate, lithium acetylacetonate,lithium bromide, lithium iodide and lithium tetrafluoroborate were alsotested, but gave less efficient catalysis (FIG. 2).

Although the mechanism of the catalysis is not elucidated, the inventorsassume that the role of lithium chloride is to activate i-PrMgCl byincreasing the nucleophilic character of the isopropyl group by forminga magnesiate species of type 6 leading to the ate-intermediate of type 7and finally to the organomagnesium species PhMgCl.LiCl (8).

The complexation of the arylmagnesium species with LiCi as indicated for8 (Scheme 6) may also be responsible for the enhanced reactivity ofthese magnesium organometallics.^([4])

As an example, the inventors found a simple procedure for catalyzing theBr/Mg-exchange reaction of aryl and heteroaryl bromides with the complexi-PrMgCl.LiCl. It allows to prepare a range of new polyfunctionalorganomagnesium compounds starting from cheap aryl and heteroarylbromides containing the most important functionalities for organicsynthesis.

EXAMPLES

Preparation of the reagent i-PrMgCl•LiCl: Magnesium turnings (110 mmole)were placed in an Ar-flushed flask with anhydrous LiCl (100 mmole) and50 ml of THF were added. The solution of i-PrCl (100 mmole) in 50 ml ofTHF was added slowly and the mixture was stirred at rt and the Grignardformation starts within a few minutes. The reaction mixture was stirredafter the completing of exothermical reaction for additional 12 h at rt.Slightly dark solution of i-PrMgCl.LiCl was transferred to a new flaskunder Ar and removed in this way from excess of Mg.

Typical Procedure. Preparation of phenyl-(4-cyanophenyl)methanol 2da

A dry and argon flushed 10 mL flask, equipped with a magnetic stirrerand a septum, was charged with 4-bromobenzonitrile (182 mg, 1 mmole).Dry THF (1 mL) was added, the reaction mixture was cooled to −7° C. andi-PrMgCl.LiCl (1 mL, 1.1 M in THF, 1.1 mmole) was then added dropwise.The Br/Mg-exchange was complete after 3 h (checked by GC analysis ofreaction aliquots, conversion more than 90%) and benzaldehyde (116.6 mg,1.1 mmole) was added. The reaction mixture was stirred for 0.5 h at −7°C. and was then quenched with sat. NH₄Cl solution (2 mL). The aqueousphase was extracted with ether (3×4 mL) and the organic fractions werewashed with brine (5 mL), dried (Na₂SO₄) and concentrated in vacuo. Thecrude residue was purified by flash chromatography (dichloromethane)yielding the benzylic alcohol (2da) as a colourless oil (169.5 mg, 81%).¹H-NMR (CDCl₃, 200 MHz): δ=7.91-7.85 (m, 2H); 7.65-7.46 (m, 3H);7.38-7.30 (m, 4H); 5.86 (s, 1H); 2.42 (s, 1H, OH).

Preparation of 3-allyl-5-bromopyridine 2ca

A dry and argon flushed 10 mL flask, equipped with a magnetic stirrerand a septum, was charged with i-PrMgCl.LiCl (1 mL, 1.05 M in THF, 1.05mmole), the reaction mixture was cooled to −15° C. and3,5-dibromopyridine (236.9 mg, 1 mmole) was then added at one portion.The temperature than increased till −10° C. and the Br/Mg-exchange wascomplete after 15 min (checked by GC analysis of reaction aliquots,conversion more than 98%), allyl bromide (140.6 mg, 1 mmole) was added.The reaction mixture was stirred for 1 h at −10° C. and was thenquenched with sat. NH₄Cl solution (2 mL). The aqueous phase wasextracted with ether (3×4 mL), dried (Na₂SO₄) and concentrated in vacuo.The crude residue was purified by flash chromatography (dichloromethane)yielding the 3-allyl-5-bromopyridine (2ca) as a colourless oil (184.2mg, 93%). ¹H-NMR (CDCl₃, 200 MHz): δ=8.48 (d, J=2.2 Hz, 1H); 8.32 (d,J=1.6 Hz, 1H); 7.61 (dd, J=2.2 Hz, J=1.6 Hz, 1H); 5.89-5.68 (m, 1H);5.08-5.01 (m, 1H); 3.32 (brd, J=6.8 Hz, 1H).

Preparation of (2-bromophenyl)(phenyl)methanone 2ka

A dry and argon flushed 10 mL flask, equipped with a magnetic stirrerand a septum, was charged with i-PrMgCl.LiCl (1 mL, 1.05 M in THF, 1.05mmole), the reaction mixture was cooled to −15° C. and1,2-dibromobenzene (235.9 mg, 1 mmole) was then added dropwise. TheBr/Mg-exchange was complete after 1.5 h (checked by GC analysis ofreaction aliquots, conversion more than 98%) and solution of CuCN.2LiCl(0.1 mL, 1.0 M in THF, 0.1 mmole) was added. After stirring for 10 minat −15° C. benzoyl chloride (140.6 mg, 1 mmole) was added. The reactionmixture was stirred for 1 h at −15° C. and was then quenched with sat.NH₄Cl solution (2 mL) and also 5 drops of concentrated NH₃ was added.The aqueous phase was extracted with ether (3×4 mL) and the organicfractions were washed with brine (5 mL), dried (Na₂SO₄) and concentratedin vacuo. The crude residue was purified by flash chromatography(dichloromethane) yielding the ketone (2ka) as a white cristals (219.3mg, 84%). ¹H-NMR (CDCl₃, 200 MHz): δ=7.86-7.78 (m, 2H); 7.68-7.56 (m,2H); 7.52-7.30 (m, 5H).

TABLE 1 Products of type 2 obtained by the reaction of theorganomagnesium reagents 3 obtained by an exchange of aryl andheteroaryl bromides with i-PrMgCl•LiCl with various electrophiles.Grignard Yield Entry reagent^([a]) Electrophile Product of type 2(%)^([b]) 1

allyl bromide

2bb 80^([c]) 3b 2

PhCOC1

2bc 77^([c]) 3b 3

t-BuCHO

2bd 94 3b 4

allyl bromide

2ca 93 3c 5

PhCHO

2da 81 3d 6

allyl bromide

2db 92 3d 7

allyl bromide

2ea 93^([c]) 3e 8

PhCOC1

2eb 87^([c]) 3e 9

allyl bromide

2fa 95 3f 10

PhCOCl

2fb 88^([c]) 3f 11

PhCHO

2ga 70 3g 12

PhSSPh

2ha 90 3h 13

PhCHO

2hb 84 3h 14

PhCOCl

2hc 81^([c]) 3h 15

ClPPh2

2ia 85^([d]) 3i 16

ClPPh2

2ja 80^([d]) 3j 17

PhCOCl

2ka 84^([c]) 3k 18

allyl bromide

2kb 92 3k 19

2kc 86^([c]) 3k 20

PhCHO

2kd 81 3k 21

PhCHO

2la 90 3l 22

PhCHO

2ma 91 3m 23

allyl bromide

2mb 93 3m 24

PhCHO

2na 94 3n 25

I(CH₂)₃CO₂Et

2nb 81^([c]) 3n 26

PhCHO

2oa 83 3o 27

t-BuCHO

2pa 92 3p 28

allyl bromide

2qa 82 3q 29

PhCHO

2ra 87 3r 30

PhCHO

2sa 81 3s 31

PhCHO

2ta 90 3t 32

PhCOCl

2ua 85^([c]) 3u 33

allyl bromide

2va 96 3v ^([a]) X × = Cl•LiCl; ^([b])Isolated yield of analyticallypure product; ^([c])The Grignard reagent was transmetalated withCuCN•2LiCl before reaction with an electrophile; ^([d])The reactionmixture was worked up oxidatively with aq. H₂O₂.

TABLE 2 Entry^([a]) Additive Equiv. Conversion. [%] 1 — — 18 2 LiBF₄ 1.0 5 3 LiBr 1.0 40 4 LiI 1.0 38 5 LiClO₄ 1.0 38 6 LiCl 1.0 70 7 LiCl 0.2522 8 LiCl 0.5 43 9 LiCl 1.5 73 10 LiCl 2.0 74 11 LiCl 1.0 84^([b])^([a])The conversion of the reaction was determined by gaschromatographical analysis of reaction aliquots; precision ±2%.^([b])The concentration of i-PrMgCl.LiCl was 2.22 M.

Example for Improved Behavior of Reagents (R¹)₂Mg.LiY:

The reaction of aryl bromide 1 with i-PrMgCl.LiCl leads only to mixture,whereas with i-PrMgCl.LiCl in THF with the addition of 15-crown-5 leadsto 91% conversion to the corresponding Grignard reagent 2.

TABLE 3 Effect of the addition of additives on the formation of 4-methoxyphenylmagnesium chloride at 25° C. after 24 h reaction time (1Msolution in THF). Entry Additive Equiv. Conversion. [%]^([a]) 1 — —  7 2LiCl 1.0 31 (iPrMgCl) 3 LiCl 1.0 32 (secBuMgCl) 39^([b]) 4 LiCl + 15-C-51.0/1.0 A: 100 B: 100 (6 h) 5 LiCl + 15-C-5 1.0/0.5 A: 88 6 LiCl +15-C-5 1.0/0.1 A: 54 7 LiCl + 18-C-6 1.0/1.0 A: 59 B: 77 8 LiCl + 12-C-41.0/1.0 A: 30 B: 28 9 LiCl + PEG250 1.0/10% vol A: 64 B: 55 10 LiCl +1.0/10% vol A: 47 MeO(CH₂CH₂O)₃OMe B: 58 11 LiCl + 1.0/10% vol A: 52MeO(CH₂CH₂O)₄OMe B: 60 12 LiCl + dioxane 1.0/10% vol A: 91 (88)^([c]) B:100 13 LiCl + dioxane 1.0/5% vol B: 70 14 LiCl + dioxane 1.0/20% vol B:100 15 15-C-5 1.0 A: 8 16 dioxane 10% vol A: 8 17 LiCl + DMPU 1.0/10%vol B: 60 18 LiCl + MTBE 1.0/10% vol B: 27 19 LiCl + TMEDA 1.0/10% volA: 68 B: 77 20 LiCl + DME 1.0/10% vol B: 70 21 LiCl + TMU 1.0/10% vol B:48 22 LiCl + NMM 1.0/10% vol B: 20 23 LiCl + DABCO 1.0/1.0 B: 11 24LiCl + DBU 1.0/10% vol B: 49 ^([a])The conversion of the reaction wasdetermined by gas chromatographical analysis of reaction aliquots;precision ±2%. ^([b])The concentration of i-PrMgCl.LiCl was 2.22 M.^([c])In brackets conversion for the reaction with filtrated reagent.

Abbreviations:

-   15-C-5: 15-crown-5-   PEG 250: Polyethyleneglycol, mean molecular weight 250 g/mol-   DMPU: tetrahydro-1,3-dimethyl-2(1H)-pyrimidinone,-   MTBE: 2-methoxy-2-methyl-propane,-   TMU: N,N,N′,N′-tetramethyl-urea,-   NMM: N-methylmorpholine-   Method A: 4-bromoanisole was added to the prestirred mixture of    secBuMgCl.LiCl and additive at 25° C.-   Method B: Additive was added to the prestirred mixture of    secBuMgCl.LiCl and 4-bromoanisole

REFERENCES

-   [1] A. Boudier, L. O. Bromm, M. Lotz, P. Knochel, Angew. Chem.,    2000, 112, 4584; Angew. Chem. Int. Ed. 2000, 39, 4414.-   [2] a) P. Knochel, W. Dohle, N. Gommermann, F. F. Kneisel, F.    Kopp, T. Korn, I. Sapountzis, V. A. Vu, Angew. Chem. 2003, 115,    4438, Angew. Chem. Int. Ed. 2003, 42, 4302; b) L. Boymond, M.    Rottländer, G. Cahiez, P. Knochel, Angew. Chem. 1998, 110, 1801;    Angew. Chem. Int. Ed. 1998, 37, 1701;-   [3] a) M. Abarbri, F. Dehmel, P. Knochel, Tetrahedron Lett. 1999,    40, 7449; for the synthesis of arylmagnesium species starting from    aryl bromides using lithium organomagnesiates for performing the    Br/Mg-exchange reaction: b) K. Kitagawa, A Inoue, H. Shinokubo, K.    Oshima, Angew. Chem. 2000 112, 2594; Angew. Chem. Int. Ed. 2000 39,    2481; c) A Inoue, K. Kitagawa, H. Shinokubo, K. Oshima, J. Org.    Chem. 2001, 66, 4333; d) A. Inoue, K. Kitagawa, H. Shinokubo, K.    Oshima, Tetrahedron 2000, 56, 9601; e) F. Trécourt, G. Breton, V.    Bonnet, F. Mongin, F. Marsais,; G. Queguiner, Tetrahedron Lett.    1999, 40, 4339. f) F. Trécourt, G. Breton, V. Bonnet, F. Mongin, F.    Marsais,; G. Quéguiner, Tetrahedron 2000, 56, 1349.-   [4] a) P. Knochel, M. C. P. Yeh, S. C. Berk, J. Talbert, J. Org.    Chem. 1988, 53, 2390; b) P. Knochel, N. Millot, A. L.    Rodriguez, C. E. Tucker, Org. React. 2001,58,417.-   [5] P. Torsten, P. Thomas, G. Guido, S. Wolfgram. Eur. Pat. Appl.    (2002).-   [6] The direct insertion of magnesium into alkenyl halides is not    stereoselective. For example, the reaction of (Z)-1-bromooctene with    magnesium in THF produces a 15:85 E:Z mixture of 1-octenylmagnesium    bromide. The same behaviour is observed for the insertion of zinc    dust into alkenyl iodides. In both cases, a radical mechanism    operates. T. N. Majid and P. Knochel, Tetrahedron. Lett., 1990, 31,    4413.-   [7] I. Sapountzis, W. Dohle, P. Knochel, Chem. Commun. 2001, 2068.

1. A reagent having the general formulaR¹(MgX)_(n).LiY wherein n is 1 or 2; R¹ is a substituted orunsubstituted C₄-C₂₄ aryl or C₃-C₂₄ heteroaryl, containing one or moreheteroatoms; linear or branched, substituted or unsubstituted C₁-C₂₀alkyl, C₂-C₂₀ alkenyl or C₂-C₂₀ alkinyl; or substituted or unsubstitutedC₃-C₂₀ cycloalkyl; X and Y are independently or both Cl, Br or I;HalO_(n), where n=3, 4; carboxylate of formula RCO₂; dialkoxide offormula LiO—R—O; RP(O)O₂; or SCOR; where R is defined as R¹ above;phosphine of formula PR₂, where R is defined as above or PR₂ representsa heterocyclic phosphine; O_(n)SR, where n=2 or 3 and R is defined asabove; or NO_(n), where n=2 or 3; or X=R¹ as defined above.
 2. Thereagent of claim 1, wherein the reagent is (R¹)₂Mg .LiY.
 3. The reagentof claim 1, wherein the reagent comprises R¹(MgX)_(n) and LiY in a molarratio of 0.05-6.0.
 4. A reagent having the formulaR¹(MgX)_(n).LiY wherein n is 1 or 2; R¹ is a substituted orunsubstituted C₄-C₂₄ aryl or C₃-C₂₄ heteroaryl, containing one or moreheteroatoms; linear or branched, substituted or unsubstituted C₁-C₂₀alkyl, C₂-C₂₀ alkenyl or C₂-C₂₀ alkinyl; or substituted or unsubstitutedC₃-C₂₀ cycloalkyl; X is Cl; Br or I; HalO_(n), where n=3 or 4;carboxylate of formula RCO₂; alkoxide or phenoxide of formula RO;dialkoxide of formula LiO—R—O; disilazide of formula (R₃Si)₂N; thiolateof formula SR; RP(O)O₂; or SCOR; where R is defined as R¹ above; linearor branched, substituted or unsubstituted C₁-C₂₀ alkyl or C₃-C₂₀cycloalkyl amine of formula RNH; dialkyl/arylamine of formula R₂N, whereR is defined as above or R₂N represents a heterocyclic alkylamine;phosphine of formula PR₂, where R is defined as above or PR₂ representsa heterocyclic phosphine; O_(n)SR, where n=2 or 3 and R is defined asabove; or NO_(n), where n=2 or 3; or X=R¹ as defined above; and Y is Cl,tert-butylate or sec-butylate.
 5. The reagent of claim 4, which isi-PrMgCl.LiCl or sec-BuMgCl.LiCl, in a molar ratio between i-PrMgCl orsec-BuMgCl and LiCl of 0.05-6.0.
 6. The reagent of claim 1, wherein theheteroatom present in the heteroaryl is selected from the groupconsisting of B, O, N, S, Se, P, F, Cl, Br, l, and Si.